Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes—constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E. Macdonald, Ann. Rep. Med. Chem., 1996, 31, 221-230).
Considerable effort has been expended in efforts to identify compounds that act as specific inhibitors of one or more isoforms of the enzyme nitric oxide synthase. The use of such compounds in therapy has also been widely claimed.
Patent application EP 0 273 658 discloses compounds of formula wherein Ar represents phenyl optionally substituted by halogen, C1 to 4 alkyl, C1 to 3 alkoxy or CF3, or optionally substituted naphthyl; R1 represents C5 to 7 cycloalkyl, thienyl, halothienyl, (C1 to 4 alkyl)-substituted-thienyl, furanyl, pyridyl or thiazolyl; and R2 and R3 are each independently H or methyl. Said compounds are potent and selective inhibitors of serotonin and norepinephrine uptake and are thereby stated to be useful in the treatment of human diseases such as anxiety, depression and obesity.
U.S. Pat. No. 4,314,081 discloses compounds of formula wherein Ar represents phenyl optionally substituted by halogen, C1 to 4 alkyl, C1 to 3 alkoxy or C3 to 4 alkenyl; or Ar represents naphthyl; and R1, R2 and R3 are each independently H or methyl. Said compounds are potent and selective inhibitors of serotonin and norepinephrine uptake and are thereby stated to be useful in the treatment of human diseases such as depression and obesity.
Patent application WO 92/19210 discloses compounds of formula wherein Ar1 and Ar2 independently represent phenyl optionally substituted by various substituents but with the proviso that at least one of Ar1 and Ar2 is substituted by at least one halogen atom; and R1 and R2 are each independently H or C1 to 4 alkyl. Said compounds are stated to be useful for imaging neurotransmitter re-uptake systems in the brain.
Patent application DE 29 07 217 discloses compounds of formula wherein Ar1 represents phenyl substituted by nitro and optionally substituted by a second substituent selected from Cl, Br, CF3, Me or OMe; Ar2 represents phenyl optionally substituted by Cl, Br or F; R1 represents H or C1 to 5 alkyl; and R2 represents C1 to 5 alkyl. The compounds are stated to be useful in the treatment of eating disorders and depression.
Patent application GB 2 060 620 discloses compounds of formula wherein Ar1 represents phenyl optionally substituted by C1 to 6 alkyl, C2 to 6 alkenyl, CF3, halogen, nitro, amino or acylamino; Ar represents phenyl substituted by at least one group selected from C1 to 6 alkyl, C1 to 6 alkoxy, CF3, nitro or amino; R1, R2 and R4 independently represent H or C1 to 6 alkyl; and R3 represents H, C1 to 6 alkyl or benzyl. The compounds are claimed to be useful as antidepressants.
Patent application GB 2 060 621 discloses compounds of formula wherein Ar represents phenyl optionally substituted by C1 to 6 alkyl or halogen; Ar1 represents phenyl substituted by NO2, amino or acylamino; R1 and R2 independently represent H or C1 to 6 alkyl. The compounds are claimed to be useful as antidepressants.
Patent application EP 3 18 727 discloses compounds of formula wherein R1 can represent optionally substituted alkyl or cycloalkyl and R2 can represent optionally substituted phenyl. The compounds prevent calcium overload in brain cells and are thus useful in the treatment of anoxia, migraine, ischaemia and epilepsy.
Patent application EP 399 504 discloses compounds of formula wherein Ar represents optionally substituted phenyl; R can also represent optionally substituted phenyl; and R1 and R2 can represent optionally substituted alkyl or cycloalkyl. The compounds prevent calcium overload in brain cells and are thus useful in the treatment of anoxia, migraine, ischaemia and epilepsy.
Patent application EP 576 766 discloses compounds of formula wherein Ar represents optionally substituted phenyl; R can also represent optionally substituted phenyl; R1 and R2 can represent optionally substituted alkyl or cycloalkyl; or the group NR1R2 represents a 5 to 7 membered ring, optionally further substituted. The compounds prevent calcium overload in brain cells and are thus useful in the treatment of anoxia, traumatic injury, neurodegenerative diseases, migraine, ischaemia and epilepsy.
Patent application EP 571 685 discloses compounds similar to those of EP 576 766 but wherein Ar represents optionally substituted furanyl, thienyl or pyrrolyl.
The present invention relates to the surprising finding that a group of phenylheteroalkylamine derivatives, including some compounds that are within the generic scopes of some of the above background art documents, are inhibitors of the enzyme nitric oxide synthase.